9, 11, 21-trichloro-16alpha, 17alpha-isopropylidene steroids of the pregnane series



United States Patent 3 211,727 9,11,21-TRICHLOR0-16a,17a-ISOPROPYLIDENE STEROIDS OF THE PREGNANE SERIES Milton Heller and Seymour Bernstein, New City, N.Y.,

assignors to American Cyanamid Company, Stamford, 5 Conn., a corporation of Maine No Drawing. Filed Feb. 12, 1964, Ser. No. 344,177

4 Claims. (CL 260-23955) This invention relates to new steroid compounds. More particularly, it relates to trichloro-16u,17a#alky1idenedioxy steroids of the pregnane series.

The novel compounds of the present invention may be illustrated by the following formula:

are divalent radicals of the group consisting of The compounds of this invention are, in general, white crystalline solid-s, relatively insoluble in water, but generally soluble in organic solvents such as lower alkanols, acetone, ethyl acetate, and the like.

The present trichloro-steroids of the pregnane series described above may be prepared by a series of reactions starting with l 1B,21-dihydroxy-16a,l7-u-is-opropylidenedioxypregn-4-ene-3,ZO-dione, as outlined in the accompany- CHzOR 3,211,727 Patented Oct. 12, 1965 ing flowsheet hereinafter and as described in the examples which follow. The :,1l,B-dichloro-l6a,l7ot-isopropylidenedioxypregnane steroids may be prepared from the cor-responding A -precursor.

The compounds of the present invention can be prepared, for example, starting with 1lfi,21-dihydroxy-16a, l7a-isopropylidenedioxypregn-4-ene-3,ZO-dione [1. Am. Chem. Soc., 81, 4573 (1959)]. The above compound can be converted into the corresponding Zl-chloro derivative by treatment with methanesulfonyl chloride and subsequently with lithium chloride to produce 2ll-chloro-l1fihydroxy-l6a,17a-isopropylidenedioxypregn-4 ene 3,20- dione II). The latter compound on treatment with N- bromoacetamide produces the corresponding M -derivative (III) which on reaction with lithium chloride in the presence of N-chl-oro-succinimide and a solvent containing hydrogen chloride produces 9a,11fl,21-tri=chloro-16a, l7u-isopropylidenedioXypregn-4 ene 3,20 dione (=IV When 2l-ohl-oro-l lfl-hydr-oxy 16a,17a isopropylidenedioxypregn-4-en-3,20-dione (in) is heated in a solvent with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone the products are 2l1-chloro-l1fl-hydroXy-16u,17a isopropylidenedioxypregna-1,4-diene-3,20-dione (V) and 21-chloro-ll13-hydroxyal6a,17u-isopropylidenedioxypregna-1,4,6-triene 3, ZO-dione (VI). The steroid 2l-chloro-l1B-hydroXy-l6a, l7a-isopropylidenedioxypregna-1,4-diene-3,20-dione (V) treated with N-bromoacetamide in a solvent produces 211- chloro-16u,17a isopropyl-idenedioxypregna 1,4,9 (l 1)- triene-3,20-dione (V H) which on treatment with lithium chloride, N-chloro-suecinimide and hydrogen chloride in a solvent produces 9oz,l1fl,21-i21'lChl0DO-l6ot,l7a-lS0p;I0pylidenedioxypregna-l,4-diene-3,20-dione (VIII). When 21- chloro-ltlfi-hydroxy-l6p,l7,8 isopropylidenedioxypregna- 1,4,6-triene-3,20-dione (VI) is treated with N-bromoacetamide in pyridine there is obtained 21-chloro-16a,l7a-isopropylidenedioxypregna-l,4,6,9(lvl)-tetraene-3,20 dione (IX) which on treatment with lithium chloride, N-chloro succinimide, and hydrogen chloride in a solvent produces 911,1 1,8,2l-trichloro-1 6a,17a-isopropylidenedioxypregna l 4,6-triene-3,20-dione (X).

The following flows-beet graphically illustrates the reactions described above.

on TIC-(\Ii o a O/ CHa f (v1) CHzCl 011,01 srael 0:0 C:

#-o CH -----0 CH3 o1- o x o 01 0 om o \CH3 (VIII) (VII) onioi 011.01 3']: =0 -0 CH3 ------0 CH o o1- o l 0 on c1 o orn (IX) The compounds of this invention are useful as topical 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.6 g.) in dianti-infiammatory agents, not having by absorption systemic activity on adrenals or thymus. Thus, these compounds may prove useful in treating allergies and dermatological disorders. The compounds of this invention may also be useful in intra-articular therapy.

The following examples describe in greater particularity the preparation of the trichloro steroids of the present invention.

' EXAMPLE 1 Preparation of I1}8-hydr0xy-I6a,I 7a-is0pr0pylidenedi0xy- 21-methanesalfonyloxypregn-a -ene-3,20-di0ne (I b) Preparation of 21 -chl0r0-1 I B-hydroxy-I 6 (1,1 7a-is0pr0pylidenedioxypregiz-4-ene-3,20-di0ne (II) A solution of 1Iii-hydroxy-16a,17a-isopropylidenedioxy-21-methanesulfonyloxypregn-4-ene-3,20-dione 1.0 g.) and lithium chloride (280 mg.) is refluxed /2 hour and then most of the solvent is removed under reduced pressure. Addition of water gives a precipitate which is collected and is recrystallized from acetone-petroleum ether (60-70 C.) to give the product, melting point 257.5 259 C. (dec.).

. EXAMPLE 3 Preparation of 21chl0r0-II}3-hydr0xy-16a,1 7u-is0pr0pylidenedioxypregna-I,4-diene-3,20-dione (V) and 21 chloro 11p hydroxy- 160:,170: isopropylidenedioxypregna-I ,4,6 -triene-3 ,2 O-dione (VI A mixture of 21-chloro-11B-hydroxy-16a,17a-isopropylidenedioxypregn-4-ene-3,20-dione (II, 2.16 g.) and oxane (20 ml.) is refluxed 20 hours. After the mixture is cooled, it is filtered from precipitated hydroquinone and the solvent is removed under reduced pressure. The glass is dissolved in methylene chloride and filtered through a pad of megnesol to remove most of the color. The solvent is removed under reduced pressure and the resultant glass is crystallized from acetone-hexane to give 21-chloro- 11/8 hydroxy 16a,17a isopropylidenedioxypregna 1,4- diene-3,20-dione (V). The melting point of the analytical sample is 297298 C.

From the mother liquors of the above crystallization 21 chloro 11 3 hydroxy 16a,17a isopropylidenedioxypregna l,4,6-triene-3,20-dione (V1) is isolated by direct crystallization, melting point 265-267 C.

EXAMPLE 4 Preparation of 21-chlor0-16u,1 7 a-isopropylidenedioxypregna-I,4,9(1 I -triene-3,20-di0ne (VII) To a solution of 21-chloro-11/3-hydroxy-16a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione (V, 0.93 g.) in pyridine (20 ml.) is added N-bromoacetamide (0.475 g.) and the resultant solution is allowed to stand in the dark 20 minutes. Sulfur dioxide is then bubbled through the solution while it is cooled in an ice-bath until the solution gives a negative starch-iodide test. Water is then added dropwise with stirring until a precipitate results. The precipitate is collected and crystallized from acetonehexane to give the product VII, melting point 259.5- 260.5 C.

EXAMPLE 5 Preparation of 9a,11fl,2I-trichloro-I 6a,] 7a-is0pr0pylidenedioxypregna-I ,4-diene-3,20-di0ne (VIII) A mixture of 21-chloro-16a,17a-isopropylidenedioxypregna-1,4,9(l1)-triene-3,20-dione (VII, 0.5 g.) lithium chloride (2 g.) and N-chlorosuccinimide (0.173 g.) in acetic acid (20 ml.) is treated with a solution of tetrahydrofuran (0.5 ml.) saturated with hydrogen chloride. The mixture is stirred in the dark for 2 hours whereupon complete solution occurred. Upon pouring the solution into ice-Water, a precipitate occurs which is collected. Crystallization from acetone-hexane gives the product VIII, melting point 228.5 -229 C.

EXAMPLE 6 Preparation of 21-chl0r0-l6u,1 7a-isopropylidenedioxypregna-1,4,6,9 (11 -tetraene-3,20-di0ne (IX) A solution of 21-chloro-11/8-hydroxy-16u,17a-isopropylidenedioxypregna-1,4,6-triene-3,20-dione (VI, 1.1 g.) in pyridine (25 ml.) is treated with N-bromoacetamide (0.63 g.) and Worked up as in Example 4. The resultant product IX is crystallized from acetone-hexane, melting point 227.5228.5 C.

EXAMPLE 7 Preparation of 9a,11[3,21-trichl0r0-16a,] 7a-isopropylidenedioxypregna-Z ,4,6-triene-3,20-di0ne (X) A mixture of 21-chloro-16a,17a-isopropylidenedioxypregna-l,4,6,9(11)-tetrane3,20-dione (IX, 0.5 g.), lithium chloride (2 g.) and N-chlorosuccinimide (0.173 g.) in acetic acid (20 ml.) and tetrahydrofuran (0.5 ml.) saturated with hydrogen chloride is stirred 40 minutes in the dark and worked up as in Example 5. The product X is crystallized from methanol-Water, melting point 223 223.5 C.

EXAMPLE 8 Preparation of 21-chl0r0-16a,17a-is0pr0pylidenedi0xypregna-4,9 (11 )-diene-3,20-di0ne (III) A solution of 21-chloro-1lfi-hydroxy-l6a,l7a-isopropylidenedioxypregn-4-ene-3,20-dione (II, 1.87 g.) in pyridine (20 ml.) is treated with N-bromoacetamide (0.88 g.) and Worked up as in Example 6. The product III is crystallized from acetone, melting point 279-282 C.

EXAMPLE 9 Preparation of 9a,] 15,21 -trichl0ro-16a,1 7u-is0pr0pylidenedioxypregn-4-ene-3,20-di0ne (IV) A mixture of 21-chloro-16a,17a-isopropylidenedioxypregna-4,9(11)-diene-3,20-di0ne (III, 1.0 g.), lithium chloride (4 g.) and N-chlorosuccinimide (0.35 g.) in

1 wherein Cl I C and 1 0a are divalent radicals selected from the group consisting of CH CH and CH=CH- and when c. is -CH=CH then l a is CH=CH-.

2. The compound 9a,11fl,21-trichloro-16a,17a-isopropylidenedioxypregn-4-er1e-3,20-dione.

3. The compound 9a,115,2l-trichloro-l6a,17a-isopropylidenedioxypregna-1,4-diene-3,20-dione.

4. The compound 9a,115,21-trichloro-16u,17u-isopropylidenedioxypregna-l,4,6-triene-3,20-dione.

No references cited.

LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,211,727 October 12, 1965 Milton Heller et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 15 to 25, for the left-hand portion of the formula reading read columns 1 and 2, the formula numbered "(VI)" should be renumbered as formula (IV) column 2, formula (III) strike out "H8"; column 6, lines 20 to 23, the left-hand formula should appear as shown below instead of as in the patent:

Signed and sealed this 24th day of May 1966.

(SEAL) Attest:

EDWARD J. BRENNER ERNEST W. SWIDER Commissioner of Patents Attesting Officer 

1. A STEROID OF THE FORMULA: 